Overview

Contraindications

Other considerations:
- Is the drug truly needed (no suitable alternative)?
  - Are the alternatives potentially more toxic or less effective?
- Do the available tests lack high negative predictive value?
- What is individual risk-benefit?

Synonyms: drug provocation test, graded dose challenge, incremental challenge, test dosing
Objective is to cautiously introduce a drug in patients who are unlikely to be allergic to it
Drug is given in 2-3 steps (>4-5 steps may induce modifications of immune effector cells and therefore induce tolerance in the patient)
Protocols
- Should be done under close monitoring with 1:1 nursing and rescue medications readily available
- Choose starting dose:

Likelihood of true allergy to drug-------	Starting dose
Unlikely	1/100 or 1/1000th of final dose-------
Very unlikely	1/10 of final dose
Extremely unlikely	Full dose to negate history

Interval between doses depends on history of original reaction
- Immediate - 20-30 minutes
- Delayed - hours-days
The Brigham and Women’s Hospital protocol involves giving 1/10th the final therapeutic dose over 3 rapid intervals followed by administering the rest of the dose at an infusion rate of 80 mL/h
Boston Children’s Hospital protocol starts at 1/100th, then 1/10th, and finally 9/10th of the therapeutic dose given at 30 min intervals administered at the usual recommended infusion rate of the drug. The patient is then observed for 1 hr after the final dose.
If the graded challenge is tolerated, the patient may return to regular administration of the the drug

Consider risk stratification according to the severity of the patient's reaction history
Adults:
- ICU for patients with history of grade 3 reactions and/or those with minimal cardiopulmonary reserve capacity
- Outpatient infusion setting is acceptable for adults with history of grade 1-2 provided there is appropriate nursing/physician supervision
Children:
- ICU step down unit for history of grade 1-2 reactions
- ICU for grade 3 reactions

Premedication	Adults	Children	Note
Diphenhydramine	25 mg PO/IV	1 mg/Kg PO/IV	20 min prior to infusion Because most reactions tend to occur toward the end of most desensitization protocols, it may be more advantageous to premedicate with 2nd/3rd generation antihistamines with longer half-lives over shorter-acting first-generation antihistamines
Famotidine	20 mg PO/IV	20 mg IV if >12 yo	20 min prior to infusion
Ranitidine	50 mg IV	1.5 mg/Kg IV	20 min prior to infusion
Dexamethasone	20 mg PO/IV	10 mg/m2 PO/IV	Given the previous night and the morning of desensitization for certain chemotherapeutic agents
Montelukast	10 mg PO	4 mg (0-5 yo), 5 mg (6-14 yo) PO	1 hour prior to infusion Consider if previously failed desensitization or experienced flushing reactions
ASA	325 mg PO	10-15 mg/Kg PO	1 hour prior to infusion Consider if previously failed desensitization or experienced flushing reactions
Acetaminophen	500 mg PO	15 mg/Kg PO	Acetaminophen (plus histamine blockers) recommended as prophylaxis for cytokine release reactions induced by monoclonal Abs used in cancer therapy

Document any reaction, including:
- Symptoms, vital signs, peak flow, physical findings
- At what step did the reaction occur and how many minutes into the infusion
- Treatments administered, response to treatment, when the protocol desensitization was restarted
Recording time of symptom onset is helpful because a patient with a history of breakthrough reactions may receive additional antihistamine treatment before the step at which a previously experienced reactions occurred

Patients who have had severe anaphylactic reactions or who have reacted early in the standard 12-step desensitization (outlined in the spreadsheet above) may experience fewer symptoms if desensitized using a 16-step protocol, which adds another bag containing 1/1000th of the full dose. The use of a 16-step (four bags) or a 20-step (five bags) protocol is reserved for high-risk patients

Mild/moderate reactions

Pruritus, flushing, urticaria, nausea, abdominal pain, back pain*, normal vital signs
- Back pain typically only seen with chemotherapy or monoclonal antibody drugs

Stop the infusion and treat with IV diphenhydramine (25-50 mg adults, 1 mg/Kg children) and IV ranitidine (50 mg adults, 1.5 mg/Kg children)
- For shortness of breath, chest tightness, throat tightness add nebulized albuterol +/- IV methylprednisolone 0.5 mg/Kg
Observe the patient until reaction subsides and then resume protocol at the point where the infusion was stopped

Severe reactions

Syncope, hypotension, stridor, upper airway compromise, status asthmaticus, respiratory distress, hypoxia

Stop the infusion and treat with epinephrine (0.3 mg IM adults, 0.01 mg/Kg children), diphenhydramine IV and methyprednisolone IV, oxygen, nebulized albuterol for bronchospasm, and IV fluids
Consider glucagon 1-2 mg bolus IV it patient has taken beta-blockers followed by infusion at 1-5 mg/hr
Immediately alert the house-staff and or allergist on call
When the patient is stable, the protocol may be resumed as instructed by allergist on call
- When resuming, decrease the next dose at least 10-fold and repeat until no systemic reactions are observed
- In some instances, the desensitization procedure may have to be aborted, and repeated in the future with a more conservative protocol or additional premedications

HSR - hypersensitivity reaction
(Castells 2009)

Note:

For medications given at intervals significantly greater than their half-lives, such as monoclonal antibodies and chemotherapy, desensitization needs to be repeated for each administration
Severe back or chest pain and a vague sense of impending doom have been described by patients who experience acute drug reactions to chemotherapy and monoclonal antibodies (especially taxanes)
Liposomal doxorubicin adverse effects can mimic hypersensitivity reactions and can present as palmoplantar erythrodysesthesia (“hand-foot syndrome”), stomatitis, and/or a diffuse follicular eruption with an intertriginous distribution
In the largest case series of rapid desensitizations to chemotherapeutic drugs: 67% proceeded without reaction, 27% had mild reactions (no chest pain, hypotension, dyspnea, hypoxia, or throat tightness), and 6% had severe reactions (no intubations or deaths, only 1 required epinephrine)
Clinical efficacy of short half-life chemotherapeutic drugs delivered slowly via desensitization (vs. normal delivery which should achieve higher peak serum levels) is unclear